The q25 region of chromosome 6 on the human genome encodes a VIP family member that is 170 amino acids long which becomes post-translationally cleaved to form vasoactive intestinal peptide (VIP). The active form of the VIP polypeptide is a 28 amino acid protein that functions, among other ways, to reduce arterial blood pressure, to increase vasodilation of blood vessel walls, to relax smooth muscle in the respiratory system and gastrointestinal tissues, reduce inflammatory responses through both promotion of Th2 differentiation as well as the reduction of Th1 responses, modulate both the innate and adaptive immune response, and to stimulate secretion of electrolytes in the gut. VIP has also been shown to be active in the central nervous system as a neurotransmitter and in communication with lymphocytes.
VIP family members have short half-lives. For instance, VIP has a half-life of about two minutes in the blood stream. It is desirable to identify polypeptides that mimic the function of VIPs such as VIP, but have increased half-life and equivalent or more receptor selectivity than the naturally occurring VIP amino acid sequence.
Bioactivity of VIP is transmuted through three known receptor subtypes: VIP1R, VIP2R, and PAC1R. These receptors are known to induce cAMP concentration as well as stimulate the production of intracellular calcium. Their affinities for VIPs such as VIP vary depending upon the subtype and the amino acid sequence of the ligand. VPAC1 has been implemented in cancer as well as inflammatory diseases such as multiple sclerosis, arthritis, parkinson's disease and alzheimers. VPAC2R dysfunction has been implemented in neurodegenerative disorders, diabetes, and pulmonary arterial hypertension (PAH), among other disorders. It desirable to identify a peptidomimetic of VIP to have selectively antagonize or affect one VIP receptor subtype over another VIP receptor subtype in order to treat a disease related to the biological affects of one receptor without disrupting or otherwise interfering with the normal biological affects of another receptor with the same ligand.